L-ascorbic acid is a bioactive material having a strong anti-oxidative activity, which has been used as a medicine for treating scurvy and at the same time applied to cosmetics owing to its wide physiological activities including inhibiting the accumulation of melanic pigments, known as a cause of chloasma or freckles. In addition, owing to its effects of increasing collagen bio-synthesis and stimulating fibroblast growth, L-ascorbic acid has also been used to prevent browning of food, preserve incense and maintain freshness.
However, the ascorbic acid is easily oxidized by heat, light and oxygen in the air to lose its activity and is insoluble in oil, so that it has been limited in use.
In particular, the ascorbic acid is more easily oxidized in water phase. Thus, when it is included in a medicinal compound, cosmetics and food, its titer is decreased and discoloration is observed during the production processes or long term storage.
To improve stability of the ascorbic acid, numbers of ascorbic acid derivatives have been developed, and particularly studies on 3-substituted ascorbic acids have been focused on L-ascorbic acids with the substitution of the 3rd hydroxyl group (OH) with lower alkyl, lower alkylcarbonyl, or lower alkenyl.
The preparation of ascorbic acid derivatives by alkylation of an ascorbic acid is described in US Patent No. 4552888, Can. J. Chem., 43, 450 (1965) and J. Med. Chem., 31, 793 (1988). According to these descriptions, ascorbic acid is reacted with sodium methoxide (NaOMe) in such a solvent as dimethylsulfoxide (DMSO) or dimethylformamide (DMF) to give ascorbic acid sodium salt, which would be reacted with alkylhalide. However, according to the method, the substitution of the 3rd hydroxyl group of the ascorbic acid with alkyl is limited and the generation of byproducts is another problem.
The limitation of DMSO or DMF in use is further attributed to its high boiling point along with that the 3-substituted ascorbic acid derivative is highly soluble in a polar solvent, making purification very difficult (column chromatography has to be necessarily used in most cases) and providing low yield.
As an effort to overcome the above problem of the conventional method, Japanese Laid-Open Patent Publication No. S 58-57373 describes that the 5th and the 6th hydroxyl group (OH) of L-ascorbic acid are protected by isopropylidene group and 5,6-O-isopropylidene ascorbic acid, the precursor thereof, is synthesized (step 1). In step 2, alkylhalide is reacted with 5,6-O-isopropylidene ascorbic acid to give 3-O-alkyl-5,6-O-isopropylidene ascorbic acid. In step 3, to recover the original hydroxyl groups at the 5th and the 6th position of 3-O-alkyl-5,6-O-isopropylidene ascorbic acid, the generated protecting group is broken by hydrogenation (hydrolysis), resulting in 3-O-alkyl-ascorbic acid. However, in step 3, the use of a strong polar solvent results in the decrease of yield.
Korean Patent Publication No. 2001-70672 and No. 2004-88312 describe a method for preparing 3-O-substituted ascorbic acid comprising the following steps.

However, the low yield of alkylation of 3-hydroxyl group and sub-reactions caused by the overuse of alkylhalide were pointed out as disadvantages of the method with the request of the elaborate purification of produced 3-O-alkyl-5,6-O-isopropylidene ascorbic acid.